This invention is in the area of synthetic organic chemistry, and is in particular an efficient, cost effective process for the deoxygenation of the 2'-or 3'-position of a nucleoside that avoids N-alkylation. 2'- or (3'-) Deoxynucleosides prepared according to this method can be used as intermediates in the manufacture of a wide range of synthetic nucleoside derivatives, including the pharmaceutically important 3'-substituted-2',3'-dideoxynucleosides
A nucleoside is a molecule consisting of a 5-carbon sugar and a purine or pyrimidine base. Addition of a phosphate group to the 5' position of the nucleoside converts the nucleoside into a nucleotide. Natural nucleotides are the building blocks for the nucleic acids, RNA (ribonucleic acid) and DNA (deoxyribonucleic acid).
In 1985, it was reported that the synthetic nucleoside 3'-azido-3'-deoxythymidine (AZT) inhibits the replication of human immunodeficiency virus type 1 (referred to below as HIV). Mitsuya, H., et al., Proc. Natl. Acad. Sci. U.S.A. 82, 7096 (1985). HIV is believed to cause acquired immunodeficiency syndrome (AIDS). Since then, a number of other 3-substituted-2',3'-dideoxynucleosides having anti-HIV activity have been identified, including 3'-azido-2',3'-dideoxyuridine (referred to as AZDU, or CS-87), 3'-azido-2',3'-dideoxycytidine (CS-91), 3'-azido-5-methyl-2',3'-dideoxycytidine (CS-92), 5-ethyl-3'-azido-2',3'-dideoxyuridine (CS-85), and 3'-fluoro-3'-deoxythymidine (FDT).
Deoxynucleosides have historically been prepared by either of two routes; condensation of a deoxy sugar moiety with a nitrogenous base, or deoxygenation of a preformed nucleoside.
Synthetic schemes for the preparation of nucleoside derivatives from preformed nucleosides include those described by: Dyatkina, N. B., Soviet J. Biorg. Chem. 12, 563 (1986); Colla, et al., Eur. J. Med. Chem. - Chim. Ther. 20(4), 295 (1985); Herdewijn, et al., J. Med. Chem. 30, 1270 (1987); Horowitz, et al., J. Org. Chem. 29, 2076 (1984); Krenitsky, et al., J. Med. Chem. 26(6), 891 (1983); and Webb, et al., Nucleosides and Nucleotides 7(2), 147 (1988).
The original syntheses of 3'-azido and 3'-amino analogs of 2',3'-dideoxythymidine, 2',3'-dideoxycytidine, and 2',3'-dideoxyuridine were reported by Lin and Mancini in 1983. Lin, T. S., and Mancini, W. R., J. Med. Chem. 26, 544 (1983). The first step in the Lin scheme is the mesylation of the 3'-position of 5'-protected thymidine or 2'-deoxyuridine. Treatment with base provides the 2,3'-anhydro nucleoside derivative, that is acidified and again mesylated to form the 1-[2-deoxy-3-O-methanesulfonyl-5-O-(protected)-.beta.-D-threopentofuranosy l]nucleoside. This compound is then reacted with azide ion and deprotected to produce a 3'-azido-3'-deoxythymidine or 3'-azido-2',3'-dideoxyuridine. 3'-Azido-2',3'-dideoxycytidine was prepared by converting the pyrimidine carbonyl of 3'-azido-2',3'-dideoxyuridine to an amino function. The 3'-amino analogs were prepared by reduction of the 3'-azido moieties.
While the Lin and Mancini reaction scheme is suitable for the industrial preparation of 3'-substituted-2',3'-dideoxynucleosides, it is limited because the starting material, 2'-deoxynucleoside, is difficult to obtain and expensive. For example, AZT was originally prepared from thymidine that was isolated from herring sperm, available in only limited quantities.
Prisbe and Martin, in Synthetic Communications, 15(5), 401-409 (1985), disclose a method for the preparation of 2',3'-dideoxynucleosides by the deoxygenation of a 5'-O-acetyl-2'-deoxynucleoside. The deoxygenation step was carried out by reacting the 3'-hydroxyl group of the nucleoside with N,N-thiocarbonyldiimidazole, followed by treatment with methanol to yield the corresponding methylthionocarbonate. Reduction of the thionocarbonate with tri-n-butyl tin hydride provided the desired 2',3'-dideoxynucleoside The procedure is not suitable for manufacturing scale because N,N-thiocarbonyldiimidazole is prohibitively expensive and the thionocarbonate is difficult to purify before reduction.
Robins, et al., J. Am. Chem. Soc., 103, 932-933 (1981) disclose that nucleoside thionocarbonates can be prepared in a single step with phenoxythiocarbonyl chloride. Reduction of the thionocarbonate with tri-n-butyltin hydride provides the desired deoxynucleoside. This process is not suitable for manufacturing scale because phenoxythiocarbonyl chloride is very expensive.
Most of the other reported methods of preparation of nucleosides by derivatization of preformed nucleosides are suitable only as laboratory syntheses to obtain small amounts of compound for experimental use, but are not well suited for industrial scale preparation of the compounds, because of the number of steps required to obtain the product and the cost of the nucleoside starting material.
Synthetic schemes for the preparation of nucleoside derivatives that include the step of condensing a sugar with a nitrogenous base are described in a number of publications, including U.S. Pat. No. 4,921,950 to Wilson, U.S. Pat. No. 4,230,689 to Bobek, et al; Fleet, Son and Drome, Tetrahedron 42(2), 625 (1988); and European Patent Application No. 86307071.0 filed by the Wellcome Foundation, Limited.
As with preformed nucleosides, nucleosides prepared by condensing a sugar with a base typically contain hydroxyl groups at the 2' and or 3'-positions of the nucleoside that must be removed to provide the final 2',3'-dideoxynucleoside product.
Deoxygenation of some nucleosides can be accomplished by treating the nucleoside with an excess of carbon disulfide and an alkyl halide to form a 2'- and or 3'-bis(OC(S)(S)alkyl) derivative (referred to as a xanthate derivative) that can be deoxygenated with tri-butyltin hydride. The advantage of this method is that the reagents used to prepare the xanthate are inexpensive and readily available. However, it has been discovered by Chu, et al., (see J. Org. Chem., 54, 2217, 2218-2219 (1989), and U.S. Ser. No. 07/318,694) that when certain 5.dbd.-O-protected ribonucleosides are treated with an excess of carbon disulfide and an alkyl halide to form the xanthate derivative, the isolated product includes nucleoside that has been alkylated at the N.sub.1 position of purine or N.sub.3 position of pyrimidine. The undesired N-alkylation significantly reduces the efficiency of the reaction, and increases the cost of the final product.
The problems described above that are encountered in the preparation of pharmaceutically active nucleosides increase the cost of health care and result in shortages of severely needed antiviral compounds. Further, the high cost of the antiviral, and in particular anti-HIV, nucleosides prevents many of those in need from being able to obtain the drug.
In light of this, there is a strong need for an efficient process to deoxygenate the 2' or 3'-position of a nucleoside that does not result in N-alkylation of the nucleoside in the process. In particular, there is a need for a preparation of 3'-substituted-2',3'-dideoxynucleosides, notably 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine, that has a minimal number of steps and a high yield of product.
It is therefore an object of the present invention to provide a process for the deoxygenation of the 2' or 3'-position of a nucleoside that does not result in undesired N-alkylation.
It is another object to provide a process for the preparation of 3'-substituted-2',3'-dideoxynucleosides that is efficient and convenient.